Multiple sclerosis (MS) is the leading cause of non-traumatic physical disability for young and middle-aged adults. Worse, the disability progresses for the remainder of the individual's lifetime. Clinical research for managing MS has focused on developing and testing disease-modifying pharmacological agents. Although such agents reduce the frequency of relapses, they do not change the underlying disability. In contrast, physical therapy improves movement ability on laboratory tests in MS, but transfer of treatment benefits to the real world has only rarely been evaluated. In addition, MS involves progressive degeneration of the CNS, which is significantly related to disability. Intense motor training can significantly remodel cerebral grey matter and white matter structure in healthy individuals. However, it is unknown whether such training effects can occur in MS. Use-dependent structural remodeling of the CNS in MS could, in principle, moderate the progressive degeneration of this disorder. To address these concerns, this exploratory research program will use several recent findings from clinical research to determine whether progressive MS significantly responds to a specific form of controlled physical therapy by increasing (1) real-world functional abilities for extended periods and (2) structural neuroplasticity of the CNS as determined by quantitative MRI. The proposed research relies on the following observations: (1) Constraint-Induced Movement therapy (CI therapy) is the only treatment that has demonstrated controlled efficacy for significantly improving real-world motor disability in other chronic disorders (stroke and cerebral palsy) in randomized clinical trials. (2) CI therapy significantly increases cerebral cortical grey matter and white matter structural integrity in stroke, both of which in turn are correlated with real-world functional improvement. (3) Preliminary results from a small treatment sample indicate that CI therapy significantly improves real-world functional ability in progressive MS for extended periods without adverse events or exacerbation of fatigue. Accordingly, this 2-year Phase II exploratory clinical trial will use a within-subjects design to evaluate CI therapy effects on real-world function and structural MRI in MS. 33 persons with mild-moderate progressive MS will first undergo multiple baseline evaluations under Usual Care, followed by 2 weeks of CI therapy. Clinical evaluations and structural brain MRI measures (Voxel-Based Morphometry, Diffusion Tensor Imaging) will assess whether CI therapy significantly increases functional ability and CNS structural measures over baseline. Follow-up at 6 months will assess the retention of clinical improvements. Positive findings from this study would support later, extended Phase III randomized clinical trials in MS to improve understanding the extent to which CI therapy may benefit motor disability and moderate CNS structural degeneration in this progressively debilitating disorder. PUBLIC HEALTH RELEVANCE: The relevance of this research to public health is that it will assess the response of progressive multiple sclerosis (MS) to Constraint-Induced Movement therapy (CI therapy), a form of physical therapy that has controlled evidence of efficacy for improving motor deficit in many other neurological disorders. In addition, CI therapy has been demonstrated to produce significant remodeling of brain structure on MRI, which in turn has been correlated with improvement in daily living function. The proposed research will conduct a Phase II clinical trial to determine to what extent persons with progressive MS improve in their daily living activities after CI therapy, and whether such improvement is associated with significant structural changes in the brain on MRI.